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The case of a 13-year-old boy with tuberous sclerosis and primitive neuroectodermal tumor of bone is presented. A pathogenetic association between these two entities is postulated, the unifying underlying mechanism being a maldevelopment of the neural crest, or neurocristopathy.
We report on the clinical, morphologic, immunohistochemical, ultrastructural, and molecular cytogenetic features of a primitive neuroectodermal tumor (PNET) primarily arising in the urinary bladder. An 81-year-old man presented with lymphedema of the lower extremities, fatigue, and urge incontinence. Radiographically, a tumor filling the entire cavity of the urinary bladder and extending into the pelvic and retroperitoneal tissue was noted. Histology of tumor biopsies showed a highly cellular, focally necrotic small round-cell tumor with numerous mitoses and occasional rosette-like structures. The tumor cells displayed significant immunoreactivity for neuron-specific enolase (NSE) and the MIC2 gene product (CD99). Dense-core granules were detectable by electron microscopy. A molecular cytogenetic analysis using comparative genomic hybridization (CGH) revealed gains of the chromosomes 3p, 6, 8q, 12, 17q, and 21q. The patient died two weeks after diagnosis. To the best of our knowledge, this is the fifth reported case of a PNET of the urinary bladder, and the first that includes a molecular cytogenetic analysis based on CGH.
PURPOSE: To assess the antitumor efficacy of pharmacokinetically guided topotecan dosing in previously untreated patients with medulloblastoma and supratentorial primitive neuroectodermal tumors, and to evaluate plasma and CSF disposition of topotecan in these patients. PATIENTS AND METHODS: After maximal surgical resection, 44 children with previously untreated high-risk medulloblastoma were enrolled, of which 36 were assessable for response. The topotecan window consisted of two cycles, administered initially as a 30-minute infusion daily for 5 days, lasting 6 weeks. Pharmacokinetic studies were conducted on day 1 to attain a topotecan lactone area under the plasma concentration-time curve (AUC) of 120 to 160 ng/mL.h. After 10 patients were enrolled, the infusion was modified to 4 hours, with dosage individualization. RESULTS: Of 36 assessable patients, four patients (11.1%) had a complete response and six (16.6%) showed a partial response, and disease was stable in 17 patients (47.2%). Toxicity was mostly hematologic, with only one patient experiencing treatment delay. The target plasma AUC was achieved in 24 of 32 studies (75%) in the 30-minute infusion group, and in 58 of 93 studies (62%) in the 4-hour infusion group. The desired CSF topotecan exposure was achieved in seven of eight pharmacokinetic studies when the topotecan plasma AUC was within target range. CONCLUSION: Topotecan is an effective agent against pediatric medulloblastoma in patients who have received no therapy other than surgery. Pharmacokinetically guided dosing achieved the target plasma AUC in the majority of patients. This drug warrants testing as part of standard postradiation chemotherapeutic regimens. Furthermore, these results emphasize the importance of translational research in drug development, which in this case identified an effective drug.
OBJECTIVE: To study the diagnosis and differentiation of EW and PNET. METHODS: Fourteen cases of Ewing's sarcomas (EW) and peripheral primitive neuroectodermal tumors (PNET) were studied by light microscopy, immunohistochemistry and electron microscopy (EM). Twelve cases were followed up. Schmidt criterion was used for the differential diagnosis of EW and PNET. RESULTS: There were 6 cases of EW and 8 cases of PNET. Six of 8 PNET cases had Homer-Wright (H-W) rosettes. In this series, 12/14 cases were positive for O13 (HBA71) staining. NSE was positive in 3 cases of EW. All PNET cases were positive for neural markers, and 5 of them were positive for more than two of these markers. Electronmicroscopically, there were neurosecretory granules (4/4 cases), nerve-like protrusions and microfilaments (1/4 case) in PNET. In 3 of 6 EW and 1 of 6 PNET, PAS staining was positive. During the follow-up period from 2 months to 5 years, 3 cases with intraosseous EW remain alive and free of tumor. The remaining patients are dead or having their tumors metastasized. CONCLUSION: EW is more primitive in cell differentiation, while PNET has more neural differentiation. The presence of H-W rosettes is an important morphologic feature of PNET. To differentiate EW from PNET is of clinical significance O13 is a useful marker for the diagnosis of EW/PNET.
OBJECTIVE: The objective of this study was to describe the CT and MR appearances of primitive neuroectodermal tumors of the thoracopulmonary region (Askin tumor), which typically manifest as large tumors involving the chest wall and pleura. This rare malignant neoplasm, seen predominantly in children and young adults, originates in soft tissues of the chest wall, occasionally in bone, or, rarely, in the periphery of the lung. SUBJECTS AND METHODS: The study group included two boys and six girls, 7-18 years old, with thoracic primitive neuroectodermal tumors who had had CT and MR studies at presentation. In seven of these patients, the preoperative imaging interpretation was compared with surgical observations. RESULTS: Seven tumors were large. Unilateral chest wall involvement was seen in all eight patients, pleural involvement in seven, and rib destruction in five. All tumors were heterogeneous on CT scans and T2-weighted MR images, and seven were heterogenous on T1-weighted MR images. The smallest tumor was homogeneous on T1-weighted MR images. Seven tumors had a signal intensity greater than that of skeletal muscle on T1-weighted MR images, and seven showed hemorrhage or necrosis. Invasion of muscle in the chest wall was noted on MR images in seven patients and on CT scans in four patients. CT scans and MR images showed extension of tumor into adjacent lung in four patients but were indeterminate in three patients. One patient had no extension of tumor into adjacent lung. Pulmonary metastases were noted on MR images in one patient and on CT scans in three patients. CT and MR studies correctly showed pleural (n = 6), rib (n = 4), pericardial (n = 1), diaphragmatic (n = 1), and vertebral/spinal cord (n = 1) involvement, confirmed during surgery. CT and MR scans of five patients imaged before surgery were indeterminate for adjacent lung invasion. CONCLUSION: The described radiologic features of Askin tumors may be useful in deciding when to include this entity in the differential diagnosis. Areas of hemorrhage and necrosis in the large tumors are responsible for their heterogeneous appearance on CT scans and MR images. CT scans and MR images are complementary for determining the extent of disease. MR imaging is informative for determining invasion of chest wall muscle, whereas CT scanning is preferred for detecting small pulmonary metastases. Neither technique is adequate for predicting invasion of adjacent lung.
We describe a case of an occipital lobe primitive neuroectodermal tumor (PNET) in a 60-year-old man with immunocytochemical evidence of neuronal, glial, smooth muscle and adipose tissue differentiation in the primary tumor and its metastases. This is the first case of PNET of cerebrum in which adipose tissue and smooth muscle has been demonstrated. The possible cells of origin for these mesenchymal elements is discussed.
Supratentorial primitive neuroectodermal tumors (stPNETs) are malignant tumors. We saw within three years six children with stPNETs. In four of the six children radical resection could be achieved. All had craniospinal irradiation and chemotherapy according to the HIT-91 protocol. The two children with incomplete resection died due to tumor progression after 7 and 10 months. Two of the 4 children with complete tumor resection had local relapses 8 months after diagnosis and died after 14 and 18 months. One child had a diffuse meningeal relapse 12 months after diagnosis. Despite (high-dose) systemic chemotherapy and intraventricular mafosfamide, he died 21 months after diagnosis due to tumor although remission could be achieved. Only one child is still in remission 86 months after diagnosis.
A simple classification system for central nervous system neoplasms occurring primarily in infancy and childhood and largely composed of undifferentiated neuroepithelial cells is proposed. Classification is based upon appearance of the tumor as determined by light microscopy, immunocytochemical techniques, and ultrastructural features without consideration for site of origin. This classification is based on the concept that neoplastic transformation of primitive neuroepithelial cells in subependymal zones at all levels of the central nervous system or pineal body may develop into tumors largely composed of similar cells. It therefore seems appropriate to call these neoplasms primitive neuroectodermal tumors and to use descriptive terms to indicate the direction of cellular differentiation, when it has occurred. Proposed terminology for the five subtypes of undifferentiated neuroepithelial round cell tumors is as follows: 1) Primitive neuroectodermal tumor, not otherwise specified (PNET, NOS), 2) PNET with glial differentiation, 3) PNET with ependymal differentiation, 4) PNET with neuronal differentiation, and 5) PNET with multi- or bipotential differentiation. If the tumor is located in the cerebellum, medulloblastoma may be added in parentheses; if in the pineal body, pineal parenchymal neoplasm may be added.
Vasoactive intestinal peptide (VIP) is a neuromodulator and growth regulator in the developing nervous system. We analyzed 10 primitive neuroectodermal tumor (PNET) cell lines, 29 central PNET (cPNET) and 17 tumors of the Ewing's sarcoma/peripheral PNET family (ESFT) using reverse transcriptase-polymerase chain reaction (RT-PCR) and Southern hybridization. Each of the 10 cell lines and 86.2% of cPNET expressed mRNA for VIP receptor 1 (VIPR1) compared to 52.9% of ESFT. VIPR2 was expressed in 75.8% of cPNET, in 28.6% of ESFT and in all 10 cell lines. cPNET demonstrated high-affinity binding of 125I-VIP on quantitative autoradiography and in competitive binding assays. VIP inhibited tumor cell proliferation in a dose-dependent manner in 5 of 7 PNET cell lines. We conclude that VIPR1 and VIPR2 are highly expressed in cPNET and demonstrate that VIP is a growth modulator in these tumors.
We report two patients with renal primitive neuroectodermal tumor (PNET) in whom the diagnosis was established by both a cytogenetic and a molecular analysis. Histologically, both renal tumors were composed of uniform immature round cells with a positive immunoreactivity for O13 (p30/32 MIC2). The cytogenetic analysis with in situ hybridization (chromosome painting) demonstrated reciprocal translocation t(11;22)(q24;q12) specific to PNET in the cultured cells derived from each tumor. The reverse transcriptase-polymerase chain reaction (RT-PCR) in both tumors demonstrated EWS/ FLI-1 fusion transcripts, representing the molecular equivalent of t(11;22). A Southern blot analysis also confirmed EWS gene rearrangement in both renal tumors. In addition, the authors also established two new cell lines (designated as FU-RPNT-1 and FU-RPNT-2) from renal PNETs. When transplanted into athymic mice, FU-RPNT-1 and FU-RPNT-2 reproduced and maintained the morphologic and molecular characteristics of the original tumors. In conclusion, the detection of t(11;22) and EWS/FLI-1 fusion transcripts is considered to provide a novel adjunctive method for diagnosing renal PNET. These newly established cell lines thus may be used to investigate the biologic behavior related to renal PNETs.
BACKGROUND: The most common cytogenetic abnormality encountered in primitive neuroectodermal tumors (PNET)/medulloblastoma is loss of heterozygosity in the region of the short arm of chromosome 17. There is some evidence that supratentorial PNET has different cytogenetic markers than infratentorial PNET/medulloblastoma. Particularly, loss of 17p is more frequent in the latter than in the former. We describe a young girl diagnosed with supratentorial PNET (SPNET). Analysis of the tumor suppressor gene p53 in the tumorous tissue revealed a rare transversion mutational event of CAT to AAT in position 179 of exon 5. To the best of our knowledge, this is the first case of such a transversion at codon 179 in the p53 gene in SPNET. CASE REPORT: A 12-year-old girl was admitted with nausea, headache and vision disturbances. MRI of the brain showed a large space- occupying lesion in the right frontal lobe. Histological examination of the macroscopic resection of the tumor revealed PNET of the brain. Polymerase chain reaction-single strand conformation polymorphism analysis of all p53 exons was performed, and a unique variant of a transversion at codon 179 of exon 5 was revealed. Therapy was started according to the Children's Cancer group protocol (CCG-99702) designated for treatment of high-risk central nervous system embryonal tumors. She received an initial course of chemotherapy, consisting of cyclophosphamide and vincristine for mobilizing and harvesting peripheral blood stem cells (PBSCs). Then she was given craniospinal irradiation (3,600 cGy) with a boost to the tumor bed (1,980 cGy) and three consecutive courses of high-dose chemotherapy with carboplatin, vincristine and thiotepa/cyclophosphamide, with PBSCs support after each course. RESULTS: The patient is in complete remission 17 months after diagnosis, based on the results of physical examination and imaging studies. DISCUSSION: The mutation results in an alteration of the amino acid HIS to ASN. The amino acids surrounding position 175 play an important role in stabilizing the p53/DNA complex. There are only 12 known mutations of the reported type, and the finding of such a rare mutational event in a low-incidence p53 mutation tumor, such as SPNET, might add additional insight into the p53-SPNET relationship in tumorigenesis. Although not widely accepted, it is possible that different mutations of the p53 gene in patients with brain tumors may imply a different ultimate prognosis. In our case, we cannot exclude the fact that transversion of CAT to AAT in position 179 of exon 5 may explain prolonged survival of a patient with good response to therapy.
A 5-year-old girl and a 2-year-old boy presented with recurrent cerebral primitive neuroectodermal tumor (PNET) and were treated with intravenous administration of human fibroblast interferon (HuIFN-beta) which was continued as outpatient maintenance therapy. Both patients showed a partial response and were still alive 14 months and 2 years after diagnosis. Our results suggest that HuIFN-beta is an effective therapy for PNET, and can be used as long-term maintenance therapy without serious side effects.
We report the clinical, hematologic, and cytogenetic findings for a child with secondary myelodysplastic syndrome (MDS) after treatment for a primitive neuroectodermal tumor. At the time of conversion to MDS, conventional cytogenetics revealed an unbalanced der(6)t(1;6) that resulted in trisomy of the long arm of chromosome 1 and partial monosomy and duplication of 6p. Using alpha satellite probes, fluorescence in situ hybridization of bone marrow cells showed that the rearranged chromosome contained the centromeres of both chromosomes 1 and 6, thus forming a dic(1;6) resulting in trisomy 1q. This report is the first to describe a case of childhood secondary myelodysplastic syndrome associated with a trisomy 1q involving chromosome 6.
Cytogenetic analysis of peripheral primitive neuroectodermal tumors (PNETs) has demonstrated a consistent primary chromosomal change characterized by a reciprocal translocation t(11;22)(q24:q12). In the central nervous system PNETs, most frequent of which are the cerebellar medulloblastomas, the most prevalent chromosomal abnormalities include deletions and unbalanced translocations. The recent cloning of the t(11;22) breakpoint has revealed the fusion of the human FLI-1 gene on chromosome 11q24 with a gene EWS on chromosome 22q12 and permitted detection of fusion transcripts. Molecular genetic analysis for the presence of EWS/FLI-1 fusion transcripts by the reverse transcriptase-polymerase chain reaction has recently been applied to peripheral PNETs. In the present study, we analyzed eight central PNETs by reverse transcriptase-polymerase chain reaction for EWS/FLI-1 fusion transcripts. The tumors included six PNETs of the cerebellum, one supratentorial PNET of the frontal lobe and one PNET of the pineal region. Polymerase chain reaction analysis in all eight cases failed to reveal a t(11;22) translocation indicating that this is not a cytogenetic abnormality of the central PNETs. Reverse transcriptase-polymerase chain reaction analysis of EWS/FLI-1 fusion transcripts provides a novel adjunctive tool in the differentiation of central versus peripheral PNET.
Production of chromogranins, the acidic components of the chromaffin granules regarded as specific neuroendocrine markers, was analyzed by immunocytochemistry and hybridization (Northern blotting and in situ hybridization) in primary lesions and cell lines of Ewing's sarcomas, primitive neuroectodermal tumors (PNETs), and neuroblastomas. Antibodies and probes specific for chromogranin A (CgA), chromogranin B (CgB), and secretogranin II (SgII) were used. Ewing's sarcomas and PNETs, unlike neuroblastomas, were negative for CgA and CgB. Two primary Ewing's sarcomas, one primary PNET (an Askin tumor), and one PNET cell line (TC32) were found to strongly express the SgII gene, as shown by the presence of specific mRNA. This result supports the hypothesis that some Ewing's sarcomas represent a most primitive form of neuroectodermal tumor; in addition, it indicates a diagnostic role of SgII in cases of Ewing's sarcomas and PNETs.
All patients diagnosed with primitive neuroectodermal tumor (PNET) and extraosseous Ewing's sarcoma in one institution between 1962 and 1987 were reviewed. Of the 26 cases studied, 16 had been diagnosed originally as PNETs, seven tumors were rediagnosed as PNET or EOE by histologic review, and three tumors had an original diagnosis of extraosseous Ewing's sarcoma. To determine whether these diagnoses determine a group of tumors with unique biologic behavior and identifiable pathologic characteristics, clinical and treatment response data were compiled, and electron microscopic and immunohistochemical studies were done for those patients with adequate samples. With combined modality therapy, this group achieved a substantially shorter disease control interval than patients with disseminated osseous Ewing's sarcoma or disseminated neuroblastoma--10.8 months versus 17 months and 16 months, respectively. The pattern of relapse and distant spread also differed among these tumor types. Immunohistochemical studies (for example, neuron-specific enolase and beta 2 microglobulin) were helpful in confirming the diagnosis but were not definitive in themselves. Tentative diagnostic criteria are proposed for use in studies designed to provide further information on the nature and treatment of PNET. Some of the controversies regarding diagnosis are discussed. The authors propose a uniform approach to treatment of extraosseous Ewing's sarcoma and PNET in order to try to clarify their relation.
A retrospective historical analysis of patients under 18 years of age with the histopathological diagnosis of infratentorial primitive neuroectodermal tumor (PNET) is presented. The survey embraced two different groups of children. Group 1 was defined as those patients treated from 1972 to 1984 with surgical resection plus neuraxis radiotherapy alone. Group 2 was made up of children treated from 1990 to 1996 with the same approach but with the addition of adjuvant chemotherapy: cisplatin (day 1) and etoposide (days 1-3) every 3 weeks for 6 months. Group 1 embraced 42 children with an age range of 1-16 years (mean 6 years, SD 4.4 years). In group 2 there were 34 children, their ages ranging from 1 to 18 years (mean 7.2, SD 4.6 years). The prevalence of stages T2M0 and T3M0 was similar in both groups, but in group 1 there were 4 patients (9.5%) whose spinal fluid was positive for tumor cells (M1), while in group 2 there were 7 children (20.5%) with positive spinal fluid. There was an unequivocal initial response to treatment in 86% of these children in group 1 and in 79% in group 2. The event-free survival (EFS) was 30% at 252 months in group 1, while for group 2 the EFS was 67.6% at 63 months (P 0.002). Mortality from tumor activity was noted in 26 patients (70%) in group 1, while in group 2 mortality attributable to tumor progression was documented in 11 children (32%). We conclude that the use of adjuvant chemotherapy in these patients improves survival without any significant morbidity.
To investigate clinical features, treatment outcome and prognostic factors of pediatric supratentorial primitive neuroectodermal tumors(ST-PNETs), 28 ST-PNET cases were retrospectively analyzed. The prognostic importance of age, sex, size of tumor, M stage, extent of surgical resection, histological features, immunohistochemical labelling indices (Ki-67, p53), and apoptotic index were assessed. The mean age at diagnosis was 6.8 years, and the male-to-female ratio was 18:10. The presenting symptoms in 22 cases were increased intracranial pressure and focal neurological deficits. Gross total resection was achieved in 17 cases, near-total (>90%) resection in 3, and subtotal in 7; biopsy was performed in 1 case. The mean duration of follow-up was 37 months. For 25 patients who completed planned adjuvant therapy, the 3-year survival rate was 73%. Univariate analysis showed that the presence of tumor necrosis (P=0.002) and extent of resection (P=0.04) correlated with survival. Patients with a high Ki-67 labelling index (>10%) tended to have shorter survival (P=0.095). In multivariate analysis, tumor necrosis showed statistical significance(P=0.03).